tbuckley/cabot-search huggingface dataset:
Abstract 1477: TICRR is a prognosis biomarker associated with RNA epigenetic modification, DDR pathway, and RNA metabolism of lung adenocarcinoma
Authors: Xunbo Zheng, Jun Guan, Chenteng Chen, Li Han, Hanxing Huang
Journal: Cancer Research (2023)

Abstract Background: TOPBP1 interacting checkpoint and replication regulator (TICRR), a hub gene of the Cdk2-mediated initiation step of DNA replication, has been identified as a prognostic biomarker in papillary renal cell carcinoma (PRCC). Nevertheless, there are few studies on the comprehensive analysis between mRNA expression of TICRR and lung adenocarcinoma (LUAD). Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database of LUAD were acquired to analyze the mRNA expression between tumor and normal tissues, survival prognosis, and clinicopathology characters. The GO, KEGG, and gene set enrichment analysis (GSEA) were performed using the R package. The correlation of TICRR with immune cell infiltration, RNA epigenetic modification, DDR pathway, and RNA metabolism of LUAD were further explored using TCGA and GEO database. Results: TICRR was confirmed significantly upregulated in several cancers, like LUAD, Lung squamous cell carcinoma (LUSC), Uterine Corpus Endometrial Carcinoma (UCEC), except for Prostate adenocarcinoma (PRAD), Thyroid carcinoma (THCA), which was downregulated in tumor tissues. Cox analysis indicated the overexpression of TICRR was related to poor survival in several cancers. The KEGG enrichment showed TICRR expression positively related to cell cycle, homologous recombination, mismatch repair, DNA replication, and cysteine metabolism in LUAD. Pathway enrichment showed a close relationship with spliceosome, oxidative phosphorylation, and ubiquitin-mediated proteolysis. Immune infiltration analysis revealed TICRR expression was negatively correlated with B cell expression, immune score, stromal score, and immunostimulators like IL2 (P&amp;lt;0.001), and positively correlated with neutrophil cell expression, immune inhibitors like PD-L1 and CTLA4. Interestingly, high mRNA expression of TICRR correlates with DDR pathway signature (37 genes), 37 m6A/m5C regulated genes, and some metabolism-regulated genes. Single-cell analysis of six LUAD samples showed that TICRR was significantly enriched in macrophage and T cells. Conclusions: TICRR has been identified to be a prognosis biomarker in LUAD, which is involved in immune activation, pathway transportation, RNA modification, and tumor energy metabolism. TICRR can be used as a promising therapeutic target and prognosis indicator for LUAD. Citation Format: Xunbo Zheng, Jun Guan, Chenteng Chen, Li Han, Hanxing Huang. TICRR is a prognosis biomarker associated with RNA epigenetic modification, DDR pathway, and RNA metabolism of lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1477.
Abstract 2111: Identification of molecular markers of pseudomyxoma peritonei using integrative analysis of bulk and single cell RNA-seq data
Authors: Seong-Hwan Park, Hanyong Go, Jae-Yoon Kim, Seon-Young Kim, Jong Lyul Lee, Ye Jin Ha, Seon-Kyu Kim
Journal: Cancer Research (2023)

Abstract Backgrounds: Psuedomyxoma peritonei (PMP) is a rare colon disease, whose symptoms and treatments have been numerously investigated, however, there are insufficient known diagnostic or prognostic markers. Here, we aim to identify molecular markers exhibiting distinct characteristics of PMP. Methods: We analyzed RNA-seq data to identify gene signatures associated with PMP development using 19 fresh frozen tissue samples including 12 PMPs (discovery cohort). For validation, we applied those signatures into an independent cohort containing 34 formalin-fixed paraffin embedded (FFPE) samples including 25 PMPs (validation cohort). We also verified protein expression levels in the signature using immunohistochemical staining (IHC) in other independent cohort in PMP. Additionally, a transcriptomic profiling using single-cell RNA-seq was carried out to confirm the cell type-specific gene expression patterns in a separated patient group with five PMPs. Results: In the discovery cohort of fresh-frozen tissues, unsupervised hierarchical clustering analysis exhibited a distinct gene expression pattern clearly dichotomizing normal and PMP samples. Genes involved in cell movement or immune response were highly expressed in PMPs. Interestingly, we found that PMP disease had a molecular heterogeneity showing epithelial as well as mesenchymal characteristics, in which both CDH1 and CDH2 were significantly elaborated in PMPs. We also estimated protein expression levels of PMP-associated key markers using IHC, in which a significant positive correlation between transcript and protein expressions in CDH1, whereas we could not observe such a significance but a clear tendency toward highly expression of CDH2 in PMPs. However, in a single-cell RNA-seq analysis, we discovered distinct eight cell type-specific clusters including an epithelial cell group, in which CDH1 was highly expressed, and a mesenchymal cell group, in which CDH2 showed a significant higher expression pattern, suggesting that PMP show dual molecular characteristics of epithelial as well as mesenchymal. Conclusion: We explore genetic characteristics and suggest key markers of PMP development. Our findings would be practically utilized for clinical practice in PMP diagnosis or prognosis. Citation Format: Seong-Hwan Park, Hanyong Go, Jae-Yoon Kim, Seon-Young Kim, Jong Lyul Lee, Ye Jin Ha, Seon-Kyu Kim. Identification of molecular markers of pseudomyxoma peritonei using integrative analysis of bulk and single cell RNA-seq data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2111.
Abstract 5257: Activation of NRF2-mediated oxidative stress response pathway by curcumin analog FLLL12: Implication for chemoprevention
Authors: Raji Lukmon, Adeoluwa A. Adeluola, A.R.M. Ruhul Amin
Journal: Cancer Research (2023)

Abstract Purpose: Carcinogenesis is a multi-step complex process initiated with irreversible genetic mutation due to endogenously derived or carcinogen-induced oxidative stress. Activation of the antioxidant pathways ameliorates oxidative stress, protects cells from carcinogenic insults, and plays a pivotal role in chemoprevention. We have previously reported that FLLL12 is a potent curcumin analog, possesses in vitro and in vivo anticancer activity, and has better pharmacokinetic profiles than curcumin. The purpose of the current study is to identify novel pathways activated by FLLL12 using RNASeq analysis. Methods: MDA686, a head and neck cancer cell line, were treated with 2 µM FLLL12 for 24h. Total RNA was isolated and used for RNASeq analysis. 2-fold differentially expressed genes were used for Ingenuity Pathway Analysis to identify the most significantly affected pathways. Real-time qPCR and western blotting were used to confirm the expression of the genes associated with the most significantly affected pathways and their protein products respectively in normal, premalignant, and malignant cell lines. Results: Whole transcriptome analysis using RNASeq identified 641 genes that were either upregulated or downregulated by 2-folds after FLLL12 treatment. Enrichment of this gene set with Ingenuity Pathway Analysis identified the ferroptosis signaling pathway, the tumor microenvironment pathway, and the NRF2-mediated oxidative response pathway as the top three most significantly affected pathways by FLLL12. We confirmed the activation of HMOX-1, NQO1, SLC7A11, and GCLC mRNA and proteins in HOK (normal), MSK-LEUK1 (premalignant), and MDA686TU (malignant) cells. Although these genes are common for the ferroptosis signaling pathway and the NRF2-mediated oxidative response pathway, treatment of cells with ferroptosis inhibitors, ferrostatin 1, and deferoxamine, had no effect on FLLL12-induced cell death suggesting that these genes are associated with oxidative stress response pathway. Conclusions: Our results strongly suggest that FLLL12 activates the oxidative stress response pathway in normal, premalignant, and malignant head and neck cancer cell lines and has strong promise for chemoprevention. Citation Format: Raji Lukmon, Adeoluwa A. Adeluola, A.R.M. Ruhul Amin. Activation of NRF2-mediated oxidative stress response pathway by curcumin analog FLLL12: Implication for chemoprevention. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5257.
Abstract 2011: Polycondensate-epitope vaccine augments anti-cancer T lymphocyte responses and induces long-term immune memory
Authors: Xiaomeng Hu, Li Tang
Journal: Cancer Research (2023)

Abstract Background: Personalized cancer vaccines are promising treatments to induce or augment antitumor responses. Despite the observed benefits in early-phase clinical studies, the clinical efficacy of cancer vaccines remains modest. Here, we aim to develop a vaccine delivery strategy to enhance the antitumor efficacy of cancer vaccines. Method: We developed polycondensate-epitope vaccines (PEVs) for co-delivering of major histocompatibility complex (MHC) I and II-restricted peptides (OVA257-264 and OVA323-339) to elicit antigen-specific CD4+ and CD8+ T cells for long-term antitumor immunity. PEVs were prepared by polymerizing amino-functionalized MHC I and MHC II-restricted peptides with a TLR1/2 agonist, Pam3CSK4, using a responsive linker. We characterized the physical properties (size, MW) and responsiveness of the prepared PEVs. The immunogenicity was evaluated in mice via flow cytometry and ELISpot assay. We finally assessed the antitumor efficacy in both prophylactic and therapeutic tumor models. Results: The prepared PEVs have an average size of 20 nm to 50 nm, &amp;gt;95% incorporating efficiency, and a remarkably high loading capacity of antigens and adjuvants (57.18~ 61.3 wt/wt %). PEVs consisting of both MHC I and MHC II-restricted OVA peptides induced robust antigen-specific CD4+ and CD8+ T cell responses and long-term memory immune response against tumors. The vaccine-induced CD8+ and CD4+ T cells exhibited high proliferative capacity and polyfunctionality upon antigen restimulation ex vivo. In a prophylactic model, mice immunized by PEVs completely rejected the first and the second challenge of YUMM1.7-OVA tumor cells with 100% rejection rate. In a therapeutic model, treatment with PEVs loaded OVA257-264 and OVA323-339 peptides induced marked tumor regression in mice bearing established YUMM1.7-OVA tumors showing enhanced anti-tumor efficacy as compared to PEVs loaded with CD8 epitope alone. Conclusion: Our results demonstrate that PEV is a promising vaccine delivery strategy for eliciting highly effective and durable anti-cancer immune responses. Citation Format: Xiaomeng Hu, Li Tang. Polycondensate-epitope vaccine augments anti-cancer T lymphocyte responses and induces long-term immune memory [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2011.
Abstract 5215: Clinical features of Li-Fraumeni syndrome in Korea
Authors: Ran Song, Seeyoun Lee, Jai Hong Han, Jae Yeon Woo, Min Jung Lee, Han-Sung Kang, Sunhwa Park, Eun-Gyeong Lee, Sun Young Kong, So-Youn Jung
Journal: Cancer Research (2023)

Abstract Purpose: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant hereditary disorder caused by a germline mutation in the TP53 gene. Because of the rarity of the disease, there were limited data on the types of the mutation, clinical features and treatment outcomes. The aim of this study is to evaluate the clinical characteristics and prognosis in Korean patients with germline TP53 gene mutation. Methods: Patients who underwent genetic counseling and confirmed with TP53 gene mutation in National Cancer Center in Korea between 2011 and 2022 were reviewed retrospectively. Data on family history with pedigree, types of mutation, clinical features and prognosis were collected. Results: Fourteen patients with LFS were included in the study. Missense mutations were shown in 13 cases and nonsense mutation in 1 case. The repeated mutations were p.Arg273His (n=2), p.Ala138Val (n=2) and pPro190Leu (n=2). A sister with breast cancer had the same mutation of p.Ala138Val. The median age at diagnosis of first tumor in 14 LFS patients was 32 (1-67) years. Seven patients (50%) had multiple primary cancers. Breast cancer was most frequently observed (n=9) and other types of tumor included sarcoma (n=5), thyroid cancer (n=3), pancreatic cancer (n=2), ovarian cancer (n=1), endometrial cancer (n=1), colon cancer (n=1), brain tumor (n=1), adrenocortical carcinoma (n=1), vaginal cancer (n=1), skin cancer (n=1) and leukemia (n=1). The median follow-up period was 51.5 (6-188) months. There were two cases of local recurrence and four cases of distant metastasis during the periods. Two patients died from leukemia and pancreatic cancer at three months and 23 months after diagnosis, respectively. Conclusion: As known in other countries, many Korean patients with LFS also had an early onset and multiple primary tumors. And patients showed various types of mutation, clinical features and prognostic outcomes. Further large-scale studies are required for proper screening and management in Korean patients with LFS. Grant: This study was supported by National cancer center, Korea, Grant no. 2110181 Citation Format: Ran Song, Seeyoun Lee, Jai Hong Han, Jae Yeon Woo, Min Jung Lee, Han-Sung Kang, Sunhwa Park, Eun-Gyeong Lee, Sun Young Kong, So-Youn Jung. Clinical features of Li-Fraumeni syndrome in Korea. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5215.
Abstract 5390: Robust prediction of pan-cancer immune checkpoint blockade response using machine learning
Authors: Tiangen Chang, Saugato R. Dhruba, Yingying Cao, Luc G. Morris, Eytan Ruppin
Journal: Cancer Research (2023)

Abstract Immune checkpoint blockade (ICB) has revolutionized our approach to cancer treatment. However, the response rate is still low. With the accumulation of data, efforts to use these data to build machine learning predictors of ICB response are rising. However, as most datasets are still quite small, pertaining machine learning models may often ‘overfit’ the data, i.e., have a much weaker performance on independent test data than on the data they were learned upon. Here we analyzed ~2000 patient samples from multiple cohorts across 16 solid tumor types. Based on 10 genomic &amp; clinical features, we built different machine learning models, comparing their performance in terms of the Area Under ROC Curve (AUC) and importantly, in terms of the AUC difference between training vs validation sets, using a standard cross validation procedure. As a result, the Linear LASSO Regression (LLR) model outperformed all other models by having the highest AUC on the validation set (0.74) and notably, the smallest AUC difference between training and validation sets (0.02). In contrast, these two AUC values for the FDA approved tumor mutational burden (TMB) biomarker are 0.63 and 0.03. The highest predictive features were, receiving chemotherapy before ICB treatment or not, TMB, cancer type, blood albumin level, blood neutrophil-to-lymphocyte ratio, and patient age. The LLR score also consistently predicted overall survival and progression-free survival across all individual cancer types. More importantly, ICB response probability increased near-monotonically from 0% to &amp;gt; 43% with the LLR score, which is an important feature for patient exclusion. In contrast, ICB response probability is ~25% when TMB = 0 and not always higher with higher TMB. In summary, the LLR model identifies key features predicting pan-cancer ICB response and survival. The use of combined genomic and clinical features holds potential to further facilitate clinical ICB patient stratification beyond TMB. Citation Format: Tiangen Chang, Saugato R. Dhruba, Yingying Cao, Luc G. Morris, Eytan Ruppin. Robust prediction of pan-cancer immune checkpoint blockade response using machine learning. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5390.
Abstract 1708: Sex-biased function of an oncogene, <i>YAP1</i>, regulates medulloblastoma stem cells and immune evasion
Authors: Nourhan Abdelfattah, Sivaraman Natarajan, Jose Maldonado, Han Nhat Tran, Hannah Borland, Rachael McMinimy, Shu-Hsia Chen, Fernando Camargo, James Olson, Joshy George, Kyuson Yun
Journal: Cancer Research (2023)

Abstract Sex disparity in both cancer incidence and response to therapeutics, especially immunotherapy, has become an important area of research in recent years. Brain tumors show obvious sex biases in incidence and therapy response. Medulloblastoma (MB) is the most common malignant pediatric brain tumor, and similar to other brain tumors, males have consistently higher incidence across all subgroups and at all ages. Moreover, for patients &amp;gt;3 years of age, females have significantly better outcomes than males. However, molecular drivers of such sex disparity in incidence and prognosis remain unclear.Here, we report a male-biased function of an oncogene, YAP1, in MB formation and immune suppression. Integrated multi-platform genomic, transcriptomic, proteomic, and in vivo transcriptional target analyses show that YAP1 promotes cancer stem cell maintenance through concurrent transcriptional activation of stemness genes, such as Sox2, and repression of differentiation regulators such as NeuroD1 and Zic1/2. YAP1 expression in MB cells also inhibits anti-tumor immune cell infiltration by directly regulating Csf1, Igf1, and Igfbp3 transcription and modulating IL6-JAK-STAT3, TNFR1, TGFb, and CCL5 Pathways. Notably, we found that YAP1 genetic deletion results in disproportionately higher survival of males than females in a spontaneous mouse model of infantile SHH MB, despite equivocal expression levels in both sexes. Consistent with our findings in mouse models, YAP1 downstream genes stratify MB patient survival in males but not females. Finally, we show that a brain-penetrant YAP1 inhibitor, verteporfin, extends survival and enhances immune infiltrates in vivo, mimicking the effects of Yap1 genetic deletion. In summary, this study demonstrates that an oncogene function may be sex-biased and underscores the need to incorporate sex as a variable in cancer mechanisms, tumor immunology, and treatment response studies. Citation Format: Nourhan Abdelfattah, Sivaraman Natarajan, Jose Maldonado, Han Nhat Tran, Hannah Borland, Rachael McMinimy, Shu-Hsia Chen, Fernando Camargo, James Olson, Joshy George, Kyuson Yun. Sex-biased function of an oncogene, YAP1, regulates medulloblastoma stem cells and immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1708.
Abstract 6333: Repurposing NSAIDs for chemo-immunotherapy: mechanisms beyond COX inhibition
Authors: Ogacheko D. Okoko, Md Y. Gazi, Xin Wang, Caitlin Brandle, Mercy Kehinde-Ige, Gary A. Piazza, Huidong Shi, Gang Zhou
Journal: Cancer Research (2023)

Abstract It has been well-established that some nonsteroidal anti-inflammatory drugs (NSAIDs) have antitumor activities. The beneficial effects of these NSAIDs are mainly attributed to their ability to inhibit the production and activity of cyclooxygenases (COX1 and COX2) and prostaglandin (PGE2), which are known to promote tumor progression, angiogenesis, metastasis and immunosuppression. We recently reported that administration of indomethacin, a prototypical NSAID, can enhance the antitumor efficacy of adoptive T cell therapy in animal models. However, currently adoptive T cell therapy as a treatment option is only suitable for selected patients with certain types of cancer. Here, we set out to explore the utility of indomethacin in a chemo-immunotherapy setting that is readily applicable to a wide range of cancers. Cyclophosphamide (CTX) is a widely used antineoplastic chemotherapeutic agent with immunostimulatory activities when used at low-medium doses. We show that indomethacin had no impact on tumor growth but can significantly enhance the antitumor effect of CTX in multiple mouse tumor models. The beneficial effect of indomethacin was diminished in immunodeficient mice or CD8 T cell-depleted wild-type mice, indicating the requirement for the host immunity. Furthermore, the CTX and indomethacin regimen can sensitize tumors to anti-PD1 immunotherapy. scRNAseq analysis of tumor samples revealed the impact of indomethacin on the tumor microenvironment. Our data also indicate that the immunopotentiating effect of indomethacin can be independent of PGE2 inhibition, and involves the TRAIL-DR5 axis in promoting tumor regression. Other potential mechanisms, including modulation of chronic interferon signaling in tumor cells, have also been investigated. Altogether, our study sheds light on the multiple mechanisms underlying indomethacin’s beneficial effects, and highlights the potential of NSAID administration as a readily applicable and cost-effective approach to augment the efficacy of chemo-immunotherapy. Citation Format: Ogacheko D. Okoko, Md Y. Gazi, Xin Wang, Caitlin Brandle, Mercy Kehinde-Ige, Gary A. Piazza, Huidong Shi, Gang Zhou. Repurposing NSAIDs for chemo-immunotherapy: mechanisms beyond COX inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6333.